Macrophages contribute to liver repair after monocrotaline-induced liver injury via SDF-1/CXCR4

Human amnion epithelial cells (hAECs) exert potent antifibrotic and anti-inflammatory effects when transplanted into preclinical models of tissue fibrosis. These effects are mediated in part via the secretion of soluble factors by hAECs which modulate signaling pathways and affect cell types involved in inflammation and fibrosis. Based on these reports, we hypothesized that these soluble factors may also support liver regeneration during chronic liver injury. To test this, we characterized the effect of both hAECs and hAEC-conditioned medium (CM) on liver repair in a mouse model of carbon tetrachloride (CCl4)-induced fibrosis. Liver repair was assessed by liver fibrosis, hepatocyte proliferation, and the liver progenitor cell (LPC) response. We found that the administration of hAECs or hAEC-CM reduced liver injury and fibrosis, sustained hepatocyte proliferation, and reduced LPC numbers during chronic liver injury. Additionally, we undertook in vitro studies to document both the cell–cell and paracrine-mediated effects of hAECs on LPCs by investigating the effects of co-culturing the LPCs and hAECs and hAEC-CM on LPCs. We found little change in LPCs co-cultured with hAECs. In contrast, hAEC-CM enhances LPC proliferation and differentiation. These findings suggest that paracrine factors secreted by hAECs enhance liver repair by reducing fibrosis while promoting regeneration during chronic liver injury.

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FURTHER STUDIES ON FACTORS INFLUENCING LIVER INJURY AND LIVER REPAIR

Annals of Surgery ◽

10.1097/00000658-195009000-00004 ◽

1950 ◽

Vol 132 (3) ◽

pp. 362-373 ◽

Cited By ~ 11

Author(s):

I. S. RAVDIN ◽

HARRY M. VARS

Keyword(s):

Liver Injury ◽

Factors Influencing ◽

Liver Repair

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Proper Heat Shock Pretreatment Reduces Acute Liver Injury Induced by Carbon Tetrachloride and Accelerates Liver Repair in Mice

Journal of Toxicologic Pathology ◽

10.1293/tox.2013-0006 ◽

2013 ◽

Vol 26 (4) ◽

pp. 365-373 ◽

Cited By ~ 18

Author(s):

San-Qiang Li ◽

Dong-Mei Wang ◽

You-Ju Shu ◽

Xue-Dong Wan ◽

Zheng-Shun Xu ◽

...

Keyword(s):

Carbon Tetrachloride ◽

Heat Shock ◽

Liver Injury ◽

Acute Liver Injury ◽

Liver Repair ◽

Heat Shock Pretreatment

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Macrophages promote liver repair after monocrotaline-induced liver injury via SDF-1/CXCR4 axis

Proceedings for Annual Meeting of The Japanese Pharmacological Society ◽

10.1254/jpssuppl.94.0_1-o-g1-3 ◽

2021 ◽

Vol 94 (0) ◽

pp. 1-O-G1-3

Author(s):

Yoshiya Ito ◽

Fumisato Otaka ◽

Takuya Goto ◽

Kanako Hosono ◽

Ko Hatanako ◽

...

Keyword(s):

Liver Injury ◽

Liver Repair ◽

Cxcr4 Axis

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Neutralization of ADAM8 ameliorates liver injury and accelerates liver repair in carbon tetrachloride-induced acute liver injury

The Journal of Toxicological Sciences ◽

10.2131/jts.39.339 ◽

2014 ◽

Vol 39 (2) ◽

pp. 339-351 ◽

Cited By ~ 10

Author(s):

San-Qiang Li ◽

Sha Zhu ◽

Xue-Dong Wan ◽

Zheng-Shun Xu ◽

Zhao Ma

Keyword(s):

Carbon Tetrachloride ◽

Liver Injury ◽

Acute Liver Injury ◽

Liver Repair

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Evidence for and against epithelial-to-mesenchymal transition in the liver

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00289.2013 ◽

2013 ◽

Vol 305 (12) ◽

pp. G881-G890 ◽

Cited By ~ 53

Author(s):

Guanhua Xie ◽

Anna Mae Diehl

Keyword(s):

Liver Injury ◽

Epithelial Cells ◽

Hepatic Stellate Cells ◽

Epithelial To Mesenchymal Transition ◽

Stellate Cell ◽

Stellate Cells ◽

Mesenchymal Cells ◽

Mesenchymal Transition ◽

Liver Epithelial Cells ◽

Liver Repair

The outcome of liver injury is determined by the success of repair. Liver repair involves replacement of damaged liver tissue with healthy liver epithelial cells (including both hepatocytes and cholangiocytes) and reconstruction of normal liver structure and function. Current dogma posits that replication of surviving mature hepatocytes and cholangiocytes drives the regeneration of liver epithelium after injury, whereas failure of liver repair commonly leads to fibrosis, a scarring condition in which hepatic stellate cells, the main liver-resident mesenchymal cells, play the major role. The present review discusses other mechanisms that might be responsible for the regeneration of new liver epithelial cells and outgrowth of matrix-producing mesenchymal cells during hepatic injury. This theory proposes that, during liver injury, some epithelial cells undergo epithelial-to-mesenchymal transition (EMT), acquire myofibroblastic phenotypes/features, and contribute to fibrogenesis, whereas certain mesenchymal cells (namely hepatic stellate cells and stellate cell-derived myofibroblasts) undergo mesenchymal-to-epithelial transition (MET), revert to epithelial cells, and ultimately differentiate into either hepatocytes or cholangiocytes. Although this theory is highly controversial, it suggests that the balance between EMT and MET modulates the outcome of liver injury. This review summarizes recent advances that support or refute the concept that certain types of liver cells are capable of phenotype transition (i.e., EMT and MET) during both culture conditions and chronic liver injury.

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Forkhead Box M1 Transcription Factor Is Required for Macrophage Recruitment during Liver Repair

Molecular and Cellular Biology ◽

10.1128/mcb.00876-10 ◽

2010 ◽

Vol 30 (22) ◽

pp. 5381-5393 ◽

Cited By ~ 37

Author(s):

Xiaomeng Ren ◽

Yufang Zhang ◽

Jonathan Snyder ◽

Emily R. Cross ◽

Tushar A. Shah ◽

...

Keyword(s):

Transcription Factor ◽

Liver Injury ◽

Viral Infections ◽

Inflammatory Cells ◽

Neutrophil Infiltration ◽

Hepatocyte Proliferation ◽

Forkhead Box ◽

Forkhead Box M1 ◽

Monocyte Recruitment ◽

Liver Repair

ABSTRACT Acute liver injury results from exposure to toxins, pharmacological agents, or viral infections, contributing to significant morbidity and mortality worldwide. While hepatic inflammation is critical for liver repair, the transcriptional mechanisms required for the recruitment of inflammatory cells to the liver are not understood. Forkhead box M1 (Foxm1) transcription factor is a master regulator of hepatocyte proliferation, but its role in inflammatory cells remains unknown. In this study, we generated transgenic mice in which Foxm1 was deleted from myeloid-derived cells, including macrophages, monocytes, and neutrophils. Carbon tetrachloride liver injury was used to demonstrate that myeloid-specific Foxm1 deletion caused a delay in liver repair. Although Foxm1 deficiency did not influence neutrophil infiltration into injured livers, the total numbers of mature macrophages were dramatically reduced. Surprisingly, Foxm1 deficiency did not influence the proliferation of macrophages or their monocytic precursors but impaired monocyte recruitment during liver repair. Expression of L-selectin and the CCR2 chemokine receptor, both critical for monocyte recruitment to injured tissues, was decreased. Foxm1 induced transcriptional activity of the mouse CCR2 promoter in cotransfection experiments. Adoptive transfer of monocytes to Foxm1-deficient mice restored liver repair and rescued liver function. Foxm1 is critical for liver repair and is required for the recruitment of monocytes to the injured liver.

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Proliferation of hepatic stellate cells, mediated by YAP and TAZ, contributes to liver repair and regeneration after liver ischemia-reperfusion injury

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.00153.2017 ◽

2018 ◽

Vol 314 (4) ◽

pp. G471-G482 ◽

Cited By ~ 16

Author(s):

Takanori Konishi ◽

Rebecca M. Schuster ◽

Alex B. Lentsch

Keyword(s):

Cell Proliferation ◽

Liver Injury ◽

Hepatic Stellate Cell ◽

Hepatic Stellate Cells ◽

Stellate Cell ◽

Ischemia Reperfusion ◽

Stellate Cells ◽

Hepatocyte Proliferation ◽

Binding Motif ◽

Liver Repair

Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) are key regulators of cell proliferation and organ size; however, their physiological contribution after liver injury has not been fully understood. In this study, we sought to determine the role of YAP and TAZ during liver recovery after ischemia-reperfusion (I/R). A murine model of partial (70%) I/R was used to induce liver injury and study the reparative and regenerative response. After liver injury, there was marked activation and proliferation of hepatic stellate cells. The Hippo pathway components, large tumor suppressor 1 (LATS1) and its adapter protein, Mps one binder 1 (MOB1), were inactivated during liver repair, and YAP and TAZ were activated selectively in hepatic stellate cells. Concurrently, the expression of connective tissue growth factor and survivin, both of which are YAP and TAZ target genes, were upregulated. Hepatic stellate cell expansion and concomitant activation of YAP and TAZ occurred only in the injured liver and were not observed in the nonischemic liver. Treatment of mice with verteporfin, an inhibitor of YAP and TAZ, decreased hepatic stellate cell proliferation, survivin, and cardiac ankyrin repeat protein expression. These changes were associated with a significant decrease in hepatocyte proliferation. The data suggest that liver repair and regeneration after I/R injury are dependent on hepatic stellate cell proliferation, which is mediated by YAP and TAZ. NEW & NOTEWORTHY This study is the first to assess the proliferation of hepatic stellate cells (HSCs) after ischemia-reperfusion (I/R) injury and their role in the reparative and regenerative process. Here we show that the Hippo pathway is inactivated after I/R and that Yes-associated protein/transcriptional coactivator with PDZ-binding motif (YAP/TAZ) activation is detected in HSC. HSC proliferation and expansion are prominent during liver recovery after I/R injury. Inhibition of YAP/TAZ activation with verteporfin reduces HSC proliferation and target gene expression and attenuates hepatocyte proliferation.

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